Design of New Glycomimetic DC-SIGN ligands with improved activity and metabolic stability

DC-SIGN (Dendritic Cell-Specific ICAM3 Grabbing Non integrin) is a tetrameric calcium dependent lectin that recognizes highly mannosylated glycoproteins and some fucosylated structures displayed at the surface of several pathogens.1 In particular, DC-SIGN is known to play a key role in HIV-1 transmission and in this field our group has been developing glycomimetic DC-DIGN antagonists based on the pseudo-1,2-mannobioside scaffold 1 (Figure 1a).2 Our current aim is to enhance both the metabolic stability against glycosidases and the ligands affinity towards DC-SIGN exploiting tailored structural modifications. The pseudo-thioglycoside 2 (Figure 1a) represents a very interesting candidate to generate a new class of derivatives with improved resistance to enzymatic hydrolysis.3 On the other hand, the affinity for the receptor can be increased introducing suitable fragments at position 2 of the mannose ring as in 3 (Figure 1a). This fragment should be able to engage the Phe313 residue in the protein binding site (Figure 1b). The design of fragments for 3 and the synthetic approach towards 2 will be presented.